Microbial stimulation of different Toll-like receptor signalling pathways induces diverse metabolic programmes in human monocytes

Abstract

Microbial stimuli such as lipopolysaccharide (LPS) induce robust metabolic rewiring in immune cells known as the Warburg effect. It is unknown whether this increase in glycolysis and decrease in oxidative phosphorylation (OXPHOS) is a general characteristic of monocytes that have encountered a pathogen. Using CD14 monocytes from healthy donors, we demonstrated that most microbial stimuli increased glycolysis, but that only stimulation of Toll-like receptor (TLR) 4 with LPS led to a decrease in OXPHOS. Instead, activation of other TLRs, such as TLR2 activation by Pam3CysSK4 (P3C), increased oxygen consumption and mitochondrial enzyme activity. Transcriptome and metabolome analysis of monocytes stimulated with P3C versus LPS confirmed the divergent metabolic responses between both stimuli, and revealed significant differences in the tricarboxylic acid cycle, OXPHOS and lipid metabolism pathways following stimulation of monocytes with P3C versus LPS. At a functional level, pharmacological inhibition of complex I of the mitochondrial electron transport chain diminished cytokine production and phagocytosis in P3C- but not LPS-stimulated monocytes. Thus, unlike LPS, complex microbial stimuli and the TLR2 ligand P3C induce a specific pattern of metabolic rewiring that involves upregulation of both glycolysis and OXPHOS, which enables activation of host defence mechanisms such as cytokine production and phagocytosis.

O-GlcNAc Transferase Links Glucose Metabolism to MAVS-Mediated Antiviral Innate Immunity

“…This finding is consistent with two recent studies showing that elevated aerobic glycolysis upon viral infection is important for antiviral immune responses in mouse and human cells (Bajwa et al, 2016; Jiang et al, 2016). In addition, metabolic reprogramming towards increased glucose uptake, glycolysis and PPP has been well defined in innate immune cells that are classically activated by TLR agonists or bacterial infection (Everts et al, 2014; Lachmandas et al, 2016; O’Neill and Pearce, 2016). In contrast, alternative activation of innate immune cells, known as M2 polarization and usually associated with wound healing and tissue repair, generates a metabolic signature that mainly relies on mitochondrial metabolism consuming fatty acid and glutamine (Liu et al, 2017a).…”

Toll‐like receptor 2 regulates metabolic reprogramming in gastric cancer via superoxide dismutase 2

“…Indeed, a universal increase in aerobic glycolysis has been observed in many naïve immune cells, including neutrophils, dendritic cells, and macrophages, after activation of TLRs . More recent studies have shown that a variety of microbial components can induce metabolic changes in immune cells, the precise nature of which is determined by TLR ligand, dose and cell type . For example, in human monocytes P3C stimulation enhances mitochondrial respiration, which can be inhibited by the complex I inhibitor rotenone, resulting in reduced cytokine production and phagocytic capacity; this contrasts to the suppressive effect on OXPHOS by LPS .…”

“…Separate from these cell‐autonomous effects, extrinsic factors, such as access to nutrients and oxygen, as well as interactions with immune cells and other stromal components in the tumor microenvironment, can also contribute to the reprogrammed metabolic phenotype of cancer cells . In addition, recent evidence supports the notion that microbial‐derived products can induce the metabolic reprogramming of inflammatory/innate immune cells in the tumor microenvironment, thus impacting upon host defense responses such as cytokine production and phagocytosis, which can shape tumor immunity . In this respect, considering that the gut epithelium plays a central role in mucosal immunity against microbes and can be vulnerable to neoplastic transformation, the reprogramming of metabolic pathways in tumor (epithelial) and innate immune cells by microbial components could have relevance to the pathogenesis of gastrointestinal cancers.…”

Metabolic reprogramming of host cells upon bacterial infection: Why shift to a Warburg‐like metabolism?

“…However, by using human monocytes isolated from blood, a recent report showed that a shift from OXPHOS to glycolysis was observed only in monocytes stimulated with LPS, and not in monocytes stimulated with the TLR‐2 ligand tri‐palmitoyl cysteine (Pam3Cys) or other whole‐pathogen lysates. In monocytes stimulated with Pam3Cys, increased glycolysis was accompanied by increased OXPHOS that was needed for retention of their phagocytic capacity and cytokine production . Interestingly, elevated succinate, itaconate and citrate levels were only observed in LPS‐stimulated monocytes and redirection of these TCA intermediates was not observed in Pam3Cys‐stimulated monocytes.…”